Supported by the VA Research Service.
Introduction
This textbook has thoroughly covered the current status of gout clinical practice, a subject whose nuances, with respect to evidence-based medicine, have been succinctly addressed in some major, recent reviews. This chapter focuses on the future of the diagnosis and treatment of gout.
It is often said, in many different ways, both that predictions are difficult, and that the best way to predict the future is to take an active part in creating it. As such, it is with trepidation, in early 2011, that I present my own brief treatise, thereby concluding this textbook with both prognostication and a call to arms.
Creating a Better Future of Gout Treatment
Better Use of Imaging, Biomarkers, and Quality of Life (QOL) Instruments
Further Development and Application of Imaging Modalities in Gout
Table 27-1 summarizes a proposed action plan for the field of gout, based on the foundation of clinical and translational knowledge put forward in this textbook. We are poised to redefine gout as a disease by earlier diagnosis, including in asymptomatic hyperuricemia, using inexpensive, and increasingly available, high-resolution ultrasound, and well as the dual-energy computed tomography (DECT) approach. These imaging tools also will help in better monitoring outcomes (as opposed to tracking serum urate and gouty arthritis) by visualizing tophus shrinkage and resolution. Further, these imaging approaches, especially refinement of the highly specific DECT application, could ultimately lead to better understanding of the range of tissues affected by subclinical tophi at different stages of the disease. For example, we may learn that gouty nephropathy is far more common in this era than currently appreciated. DECT and perhaps other advanced imaging approaches could unlock some of the mysteries that surround the linkage of hyperuricemia and cardiovascular disease.
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Monosodium Urate Crystal Macroaggregates at the Articular Surface in Diagnosis and Clinical Decision Making
At several junctures in this book (see Chapter 1 , Chapter 5 , Chapter 26 ) there has been discussion of the likely importance in gout, including both in diagnosis and attacks of arthritis, of changes in monosodium urate (MSU) crystal deposition at the articular cartilage surface. This clinical-pathological aspect of gout has been under-recognized in recent years. How the sentinel high resolution ultrasound finding in gout of the cartilage surface MSU crystal deposition “double contour sign” impacts on clinical decision making will be critical. Major questions will include whether how often the ultrasound can replace arthrocentesis and synovial fluid crystal analysis for diagnosis in the setting of acute gout. In addition, it is not clear whether the macroaggregates of MSU crystals in cartilage detected by ultrasound have the same implications for initiating pharmacologic urate-lowering therapy as the absolute indication of the finding of bursal, articular, and subcutaneous tophi, as well as tophi detected by erosion on plain radiography. The same questions will hold for DECT.
Biomarkers
Better monitoring of outcomes in gout, and achievement of improved outcomes, should benefit by wider application of advanced quality of life instruments, as reviewed in Chapter 18 . Furthermore, better biomarkers in gout than serum urate—C-reactive protein and possibly markers of urate oxidation such as a allantoin, for example—should allow for improved estimation of body urate load and ongoing inflammation specific to gout. A simple test to accurately estimate total body urate stores would be particularly helpful. To date, the isotope-based techniques developed to estimate total body urate burden have not proven applicable on a wide scale for clinical practice.
Identify and Validate New Targets, and Exploit Drug Combinations
Table 27-2 summarizes some novel treatment targets for gouty inflammation and hyperuricemia, and Table 27-3 lists some of the recent and current Food and Drug Administration (FDA)–registered clinical trials in gout. Many of these targets and clinical trials programs have been discussed in detail in this book, including in Chapter 3 , Chapter 4 , Chapter 5 , Chapter 10 , Chapter 12 , Chapter 15 , Chapter 16 . A prime example is the promising approach of IL-1β inhibition for gouty inflammation.
| ANTIINFLAMMATORY THERAPY |
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| URATE-LOWERING THERAPY (ULT) |
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| >100 Ongoing or Completed Clinical Trials in Gout, partially listed on clinicaltrials.gov Phase I to phase III examples:
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Other potential targets for advanced therapeutics to improve management of gouty arthritis include the process of tophus deposition itself, which likely involve both inflammation and urate transport, and may involve regulation by adaptive immunity (see Chapter 5 ). Novel targets for gout arthritis prophylaxis and treatment, also reviewed in Chapter 5 , could emerge from knowledge of the effects in experimental MSU crystal inflammation of chemokines such as interleukin (IL)-8 and MCP-1. Other targets include mast cell activation (including release of chymase), and other mechanisms (such as neutrophil elastase and proteinase 3 [PR3] release) that provide alternatives and complementation to caspase-1 for endoproteolytic conversion of pro-IL-1β to an active, mature form. Activation of C5 and assembly of the C5b-9 membrane attack complex of complement, and specific innate immune effects of TLR2 activation via free fatty acids also could be exploited in future therapies.
Combined Xanthine Oxidase Inhibitor and Uricosuric Therapy
An attractive, fundamentally synergistic ( Table 27-4 ), and increasingly applied approach to combination therapy of hyperuricemia is to use combined xanthine oxidase inhibitor (XOI) and uricosuric therapy. The rationale is robust, since XOI therapy reduces urinary uric acid excretion, and thereby limits the major, natural pathway for reduction of total body urate stores. This neglected strategy, actually dating back decades ago for severe, tophaceous gout, is receiving particularly active clinical investigation after and even used in milder cases of tophaceous gout in the 1960s and early 1970s, being “rediscovered” via preliminary, supportive findings employing submaximal probenecid with submaximal allopurinol. Such an approach can significantly increase the proportion of subjects with gout achieving a serum urate target of less than 6 mg/dl, relative to XOI treatment alone. One limitation of the approach is that probenecid increases oxypurinol clearance, and this sort of drug–drug interaction, although surmountable, needs to be considered and addressed.
Related posts:
Diagnosis of Gout
Articular Pathology of Gout, Calcium Pyrophosphate Dihydrate and Basic Calcium Phosphate Crystal Deposition Arthropathies
Gout: Epidemiology and Risk Factors
Overview of Gout Therapy Strategy and Targets, and the Management of Refractory Disease
Calcium Pyrophosphate Dihydrate Crystal Deposition: Epidemiology, Clinical Features, Diagnosis, and Treatment
Basic Calcium Phosphate Crystal Arthropathy
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